Exposure to toxic levels of lead occurs frequently and may result in pathological effects in many organs. Preliminary data from our laboratories and those of others indicate that testicular function and sperm production are affected at low levels of lead exposure. The hormonal mechanisms responsible for these effects have not been fully characterized, but our data suggest that the dominant mechanism of action of lead toxicity is at the level of the hypothalamic-pituitary axis. A combined defect involving the gonad and hypothalamic-pituitary sites is also possible. The aims of this project are: 1) To determine the time course, dose dependency and reversibility of reproductive abnormalities induced in male rats by daily exposure to lead acetate. 2) To assess the significance of age of exposure on the expression of toxicity and determine if exposure to lead from birth results in delayed puberty and/or other reproductive abnormalities. 3) To delineate mechanism(s) and site(s) of action of lead on the hypothalamic-pituitary-gonadal reproductive axis. The hypothalamus will be studied by: a) measuring GnRH responsiveness to naloxone stimulation, and b) analyzing the effect of in vivo and in vitro lead treatment on catecholamine neurotransmitter regulated release of GnRH. The pituitary gland will be examined following in vivo lead treatment by determining: a) circulating gonadotropins and prolactin, b) pituitary responsiveness to GnRH stimulation, and c) gonadotropin response to castration. The testis will be studied following in vivo lead treatment by determining: a) serum and intratesticular testosterone concentration, b) intratesticular lead levels, c) intratesticular sperm counts, d) testicular morphologic changes, and e) testicular responsiveness to LH and FSH stimulation. These studies will provide insights into the site(s) of action and mechanisms by which lead exposure alters the reproductive system in man. Such information will enhance our understanding of lead toxicity and provide potential therapeutic approaches to the pathologic consequences of lead exposure.